Epigenetic Regulation of Tumor Necrosis Factor Alpha

Sullivan, Kathleen E.; Reddy, Akhilesh B.; Dietzmann, K.; Suriano, A. R.; Kocieda, Virginia; Stewart, Mark A.; Bhatia, Mickie

doi:10.1128/mcb.02429-06

Cited by 187 publications

(164 citation statements)

References 65 publications

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“…Thus, dening the role of epigenetic regulation of TNFa may lead to new therapeutic strategies for these metabolic diseases through modulation of the inammatory status. 53 However, more detailed studies at the molecular and cellular levels are needed to determine how both extracts exert their antidiabetic activity as well as the individual compounds with an increased effect.…”

Section: Discussionmentioning

confidence: 99%

Modulation of hyperglycemia and TNFα-mediated inflammation by helichrysum and grapefruit extracts in diabetic db/db mice

et al. 2014

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Type-2 diabetes is associated with a chronic low-grade systemic inflammation accompanied by an increased production of adipokines/cytokines by obese adipose tissue. The search for new antidiabetic drugs with different mechanisms of action, such as insulin sensitizers, insulin secretagogues and aglucosidase inhibitors, has directed the focus on the potential use of flavonoids in the management of type-2 diabetes. Thirty six diabetic male C57BL/6J db/db mice were fed a standard diet and randomly assigned into four experimental groups: non-treated control, (n ¼ 8); acarbose (5 mg per kg bw, n ¼ 8);helichrysum (1 g per kg bw, n ¼ 10) and grapefruit (0.5 g per kg bw, n ¼ 10) for 6 weeks. The mRNA expression in pancreas, liver and epididymal adipose tissue was determined by RT-PCR. DNA methylation was quantified in epididymal fat using pyrosequencing. Mice supplemented with helichrysum and grapefruit extracts showed a significant decrease in fasting glucose levels (p < 0.05). A possible mechanism of action could be the up-regulation of liver glucokinase (p < 0.05). The antihyperglycemic effect of both extracts was accompanied by decreased mRNA expression of some proinflammatory genes (monocyte chemotactic protein-1, tumor necrosis factor-a, cyclooxygenase-2, nuclear factorkappaB) in the liver and epididymal adipose tissue. The CpG3 site of TNFa, located 5 bp downstream of the transcription start site, showed increased DNA methylation in the grapefruit group compared with the non-treated group (p < 0.01). In conclusion, helichrysum and grapefruit extracts improved hyperglycemia through the regulation of glucose metabolism in the liver and reduction of the expression of proinflammatory genes in the liver and visceral fat. The hypermethylation of TNFa in adipose tissue may contribute to reduce the inflammation associated with diabetes and obesity.

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Section: Discussionmentioning

confidence: 99%

Modulation of hyperglycemia and TNFα-mediated inflammation by helichrysum and grapefruit extracts in diabetic db/db mice

et al. 2014

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“…The other gene studied in this research involved in obesity development is the proinflammatory cytokine TNF-alpha, which is overexpressed in obesity and related metabolic disorders. Changes in its secretion by macrophages are mediated by epigenetic modifications that occur during the monocyte differentiation [38]. Furthermore methylation differences in TNF-alpha promoter region have been associated with distinct responses to a low-calorie diet in blood [11].…”

Section: Discussionmentioning

confidence: 99%

Leptin and TNF-alpha promoter methylation levels measured by MSP could predict the response to a low-calorie diet

et al. 2011

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Obesity-associated adipose tissue enlargement is characterized by an enhanced proinflammatory status and an elevated secretion of adipokines such as leptin and cytokines such as TNF-alpha. Among the different mechanisms that could underlie the interindividual differences in obesity, epigenetic regulation of gene expression has emerged as a potentially important determinant. Therefore, twenty-seven obese women (age: 32-50 years; baseline Body Mass Index, BMI: 34.4±4.2 Kg/m 2 ) were prescribed an eightweek Low-Calorie-Diet and epigenetic marks were assessed. Baseline and endpoint anthropometric parameters were measured and blood samples were drawn. Genomic DNA and RNA from adipose tissue biopsies were isolated before and after the dietary intervention. Leptin and TNF-alpha promoter methylation were measured by MSP after bisulfite treatment and gene expression was also analyzed.Obese women with a successful weight loss (≥5% of initial body weight, n=21) improved the lipid profile and fat mass percentage (-12%, p<0.05). Both systolic (-5%, p<0.05) and diastolic (-8%, p<0.01) blood pressures significantly decreased. At baseline women with better response to the dietary intervention showed lower promoter methylation levels of leptin (-47%, p<0.05) and TNF-alpha (-39%, p=0.071) than the non-responder group (n=6), while no differences were found between responder and non-responder group in leptin and TNF-alpha gene expression analysis. These data suggest that leptin and TNF-alpha methylation levels could be used as epigenetic biomarkers concerning the response to a Low-CalorieDiet. Indeed, methylation profile could help to predict the susceptibility to weight loss as well as some comorbidities such as hypertension or type 2 diabetes.

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“…Thus, agents produced by oxidative stress, such as ROS and RNS, cause loss of DNA methylation after mitosis, since DNMT1 does not recognize oxidized methyl groups, whereas halogen derivatives produced by inflammatory processes mimic cytosine methylation producing a gain of methylation by DNMT1 (Valinluck and Sowers, 2007). In a complex regulatory network, the expression of cytokines, such as TNF-α, is tightly regulated by epigenetic mechanisms (Sullivan et al, 2007), but cytokines, such as IL-6, regulate other genes and processes by inducing histone modifications and DNA methylation (Wehbe et al, 2006).…”

Section: Epigenetic Modificationsmentioning

confidence: 99%

Dietary factors, epigenetic modifications and obesity outcomes: Progresses and perspectives

Milagro

Mansego

Miguel

et al. 2013

Molecular Aspects of Medicine

252

161

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Nutritional factors play a life-long role in human health. Indeed, there is growing evidence that one of the mechanisms by which nutrients and bioactive compounds affect metabolic traits is epigenetics. Complex interactions among food components and histone modifications, DNA methylation, non-coding RNA expression and chromatin remodeling factors lead to a dynamic regulation of gene expression that controls the cellular phenotype. Although perinatal period is the time of highest phenotypic plasticity, contributing largely to developmental programming, also during adulthood there is evidence about a nutritional influence on epigenetic regulation. Similarly to type 2 diabetes, hypertension, atherosclerosis and other metabolic disorders, obesity predisposition and weight loss outcomes have been repeatedly associated to changes in epigenetic patterns. Different non-nutritional risk factors that usually accompany obesity seem also to be involved in these epigenetic modifications, especially hyperglycemia, inflammation, hypoxia and oxidative stress. There are currently three major objectives in epigenetic research in relation to obesity: to search for epigenetic biomarkers to predict future health problems or detect the individuals at most risk, to understand the obesity-related environmental factors that could modulate gene expression by affecting epigenetic mechanisms, and to study novel therapeutic strategies based on nutritional or pharmacological agents that can modify epigenetic marks. At this level, the major tasks are: development of robust epigenetic biomarkers of weight regulation, description of those epigenetic marks more susceptible to be modified by dietary exposures, identification of the active ingredients (and the doses) that alter the epigenome, assessment of the real importance of other obesity-related factors on epigenetic regulation, determination of the period of life in which best results are obtained, and understanding of the importance of the inheritance of these epigenetic marks.

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Epigenetic Regulation of Tumor Necrosis Factor Alpha

Cited by 187 publications

References 65 publications

Modulation of hyperglycemia and TNFα-mediated inflammation by helichrysum and grapefruit extracts in diabetic db/db mice

Modulation of hyperglycemia and TNFα-mediated inflammation by helichrysum and grapefruit extracts in diabetic db/db mice

Leptin and TNF-alpha promoter methylation levels measured by MSP could predict the response to a low-calorie diet

Dietary factors, epigenetic modifications and obesity outcomes: Progresses and perspectives

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